Possible contributions of lipoproteins and cholesterol to the pathogenesis of diabetes mellitus type 2

Eckardstein, Arnold von; Sibler, Rahel A

doi:10.1097/mol.0b013e3283412279

Cited by 127 publications

(110 citation statements)

References 51 publications

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“…Since it has been suspected that LDLR mediated lipotoxicity can alter beta cell function [6], a potential safety issue with the use of PCSK9 inhibitors is the increased risk of type 2 diabetes. However, results obtained from Pcsk9-deficient mice are discordant.…”

Section: Introductionmentioning

confidence: 99%

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

et al. 2015

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Aims/hypothesis Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study. Methods PCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline. Results Significant associations (p<10 −6 ) were found between p.R46L and lower total cholesterol (−0.394 mmol/l), LDL-cholesterol (−0.393 mmol/l) and apolipoprotein B concentrations (−0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA 1c , HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. Conclusions/interpretation The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in Electronic supplementary material The online version of this article

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Section: Introductionmentioning

confidence: 99%

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

et al. 2015

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“…Altered intracellular cholesterol homeostasis and impaired insulin secretion were observed in mice with beta-cell dysfunction for ABCA1 15 . Subjects carrying loss-of-function mutations in ABCA1 show impaired insulin secretion but not insulin resistance 34,35 . In our present study, a significant association was identified between polymorphisms within ABCA1 SNP 22 found that the ABCA1 R230C variant is associated with early-onset T2DM in the Mexican population.…”

Section: Discussionmentioning

confidence: 99%

Association of adenosine triphosphate-binding cassette transporter A1 gene polymorphism with lipid profiles and early-onset type 2 diabetes

Lu¹,

Liao²,

Wang³

et al. 2014

ScienceAsia

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Adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays an important role in lipid metabolism and is involved in diabetes. We investigated the associations between lipid profiles and an early-onset diabetic phenotype with ABCA1 genotypes among 999 type 2 diabetes mellitus patients in the Han Chinese population of Taiwan. During study enrolment, blood samples were collected by venipuncture from these patients for genomic DNA isolation and serological tests, and data related to the diabetes age of onset were collected using a self-report questionnaire. Four single-nucleotide polymorphisms (SNPs) were selected for genotyping by polymerase chain reaction in each patient. The present study found that the high-density lipoprotein (HDL) levels were significantly different among patients with different genotypes at SNP rs2487039 (p = 0.018). The body mass index (BMI) was also significantly different among patients with different genotypes at SNP rs2487039, rs2230806, and rs200069 (p = 0.009, 0.004, and 0.003, respectively). The polymorphisms at position rs10121901 in ABCA1 were statistically associated with development of early-onset type 2 diabetes mellitus (p = 0.013), with an odds ratio of 0.78 (95% confidence interval: 0.64-0.95). In conclusion, an ABCA1 variant is associated with HDL level, BMI, and early-onset type 2 diabetes mellitus in a specific Taiwanese population.

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“…Individuals with low HDL cholesterol are often insulin resistant and at increased risk of developing T2DM (Li et al 2014;von Eckardstein and Sibler 2011). T2DM, the metabolic syndrome, and IR are characterized by hyperinsulinemia and increased free fatty acids (FFA).…”

Section: Low Hdl Cholesterol Levels In Diabetes and Metabolic Syndromementioning

confidence: 99%

“…Traditionally, a reduced plasmatic level of HDL cholesterol has been interpreted to be the result of such metabolic perturbations, which are already present in the prediabetic state, and hence an innocent bystander of T2DM. However, several more recent studies suggest that HDLs help to maintain euglycemia via both insulin-dependent and insulin-independent pathways (Drew et al 2012;von Eckardstein and Sibler 2011). The infusion of artificially reconstituted HDL (rHDL) was found to improve glycemia in patients with T2DM (Drew et al 2009).…”

Section: Hdl Metabolism Subclasses and Catabolismmentioning

confidence: 99%

“…In a post hoc analysis of data from diabetic participants in the ILLUMINATE trial, the addition of the CETP inhibitor torcetrapib to atorvastatin was found to increase HDL-C and to improve glycemic control (Barter et al 2011). Several in vitro and animal experiments provided evidence that HDL improves the function and survival of beta cells as well as glucose-lowering metabolism in the muscle, liver, and adipose tissue (Drew et al 2012;von Eckardstein and Sibler 2011;von Eckardstein and Widmann 2014). In mice, the absence of ApoA-I leads to hyperinsulinemia and hyperglycemia as well as altered responses to insulin tolerance tests.…”

Section: Hdl Metabolism Subclasses and Catabolismmentioning

confidence: 99%

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HDLs, Diabetes, and Metabolic Syndrome

Vollenweider

Eckardstein

Widmann

2014

High Density Lipoproteins

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The prevalence of type 2 diabetes mellitus and of the metabolic syndrome is rising worldwide and reaching epidemic proportions. These pathologies are associated with significant morbidity and mortality, in particular with an excess of cardiovascular deaths. Type 2 diabetes mellitus and the cluster of pathologies including insulin resistance, central obesity, high blood pressure, and hypertriglyceridemia that constitute the metabolic syndrome are associated with low levels of HDL cholesterol and the presence of dysfunctional HDLs. We here review the epidemiological evidence and the potential underlying mechanisms of this association. We first discuss the well-established association of type 2 diabetes mellitus and insulin resistance with alterations of lipid metabolism and how these alterations may lead to low levels of HDL cholesterol and the occurrence of dysfunctional HDLs. We then present and discuss the evidence showing that HDL modulates insulin sensitivity, insulin-independent glucose uptake, insulin secretion, and beta cell survival. A dysfunction in these actions could play a direct role in the pathogenesis of type 2 diabetes mellitus.

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Possible contributions of lipoproteins and cholesterol to the pathogenesis of diabetes mellitus type 2

Abstract: LDL, HDL and cholesterol regulate the function and survival of β-cells. HDL also exerts antiobesity and insulin-sensitizing effects. Thus dyslipidemias may not only be consequences but also contributors to the pathogenesis and hence targets for prevention of T2DM.

Cited by 127 publications

References 51 publications

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

Association of adenosine triphosphate-binding cassette transporter A1 gene polymorphism with lipid profiles and early-onset type 2 diabetes

HDLs, Diabetes, and Metabolic Syndrome

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